Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study.

Background osteosarcoma is a rare, primary malignant bone tumour with limited available treatments for advanced or recurrent disease, resulting in a poor prognosis for patients. TAS-115 is a novel tyrosine kinase inhibitor under investigation in a phase I study in patients with solid tumours. We report data of osteosarcoma patients in the expansion cohort of this ongoing study. Patients and methods an analysis of this multicentre, open-label study was performed 6 months after the final patient was enrolled, and included patients aged ≥15 years, with unresectable or recurrent osteosarcoma, and who had refractory to standard therapy or for whom no standard therapy was available. TAS-115 650 mg/day was orally administered in a 5 days on/2 days off schedule. Results a total of 20 patients with osteosarcoma were enrolled. The most common adverse drug reactions (ADRs) were neutrophil count decreased (75%), aspartate aminotransferase increased (50%), and platelet count decreased (50%); 85% of patients had grade ≥ 3 ADRs. Long-term disease control (>1 year) with TAS-115 was achieved in three patients. The best overall response was stable disease (50%); no patient achieved a complete or partial response. Median progression-free survival was 3 months; 4-month and 12-month progression-free rates were 42% and 31%, respectively. Conclusion the safety and tolerability of TAS-115 and long-term disease stability for patients with unresectable or recurrent osteosarcoma were confirmed in this study, suggesting that TAS-115 is a promising novel therapy for advanced osteosarcoma patients. Trial registration number: JapicCTI-132333 (registered on November 8, 2013).

The Role of a Selective P2Y6 Receptor Antagonist, MRS2578, on the Formation of Angiotensin II-Induced Abdominal Aortic Aneurysms.

OBJECTIVE: The P2Y6 receptor has been shown to be involved in many cardiovascular diseases, including hypertension and atherosclerosis. The study is aimed at exploring the role of the P2Y6 receptor in Ang II-induced abdominal aortic aneurysm (AAA) formation in apolipoprotein E-deficient (apoE-/-) mice by using its selective antagonist. METHODS: Male apoE-/- mice were fed with high-fat diet and infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Mice were divided into four groups: normal saline (NS, placebo control) group (n = 8), Ang II+vehicle (Ang II) group (n = 14), Ang II-low dose MRS2578 (Ang II+MRS-16 mg) group (n = 14), and Ang II-high dose MRS2578 (Ang II+MRS-32 mg) group (n = 14). Daily intraperitoneal injection with vehicle or MRS2578 was pretreated one week before Ang II infusion. On postoperative day 10, aorta imaging of each group was taken by ultrasonography. After 4 weeks of Ang II infusion, the excised aortas were processed for diameter measurement and quantification of aneurysm severity and tissue characteristics; the blood samples were collected for measurement of the lipid profile and levels of cytokines. Verhoeff's Van Gieson (EVG) staining and immunochemistry staining were performed to evaluate disruption of the extracellular matrix (ECM) and infiltration of macrophages. Expression and activity of matrix metalloproteinases (MMPs) was measured by gelatin zymography. RESULTS: Treatment with MRS2578 made no significant difference in AAA formation, and maximal aortic diameter yet caused higher AAA rupture-induced mortality from 7% (Ang II) to 21.4% (Ang II+MRS-16 mg) or 42.9% (Ang II+MRS-32 mg), respectively (p < 0.05). Consistently, the severity of aneurysm tended to be more deteriorated in MRS2578-treated groups, especially the high-dosage group. The ratios of type III and IV aneurysm were much higher in the MRS2578-coadministered groups (p < 0.05). Furthermore, histological analyses showed that administration of MRS2578 significantly increased infiltration of macrophages, expression of monocyte chemotactic protein 1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1), and activities of MMP-2 and MMP-9 followed by aggravating degradation elastin in vivo (p < 0.05). However, the multiple effects of MRS2578 on the development of AAA are independent of changes in systolic blood pressure and lipid profiles. CONCLUSIONS: The present study demonstrated that administration of MRS2578 exacerbated the progression and rupture of experimental AAA through promoting proinflammatory response and MMP expression and activity, which indicated a crucial role of the P2Y6 receptor in AAA development. Clinical Relevance. Purinergic P2Y receptors have attracted much attention since the P2Y12 receptor antagonist had been successfully applied in clinical practice. Elucidating the underlying mechanisms of AAA and exploring potential therapeutic strategies are essential to prevent its progression and reduce the mortality rate.

Phase I study of TAS-115, a novel oral multi-kinase inhibitor, in patients with advanced solid tumors.

TAS-115 is a novel MET, VEGFR, FMS and PDGFR inhibitor, developed to improve the continuity of drug administration with a relatively short half-life. We assessed its tolerability, safety, pharmacokinetics, efficacy, and pharmacodynamics in patients with solid tumors. This open-label, dose-escalation phase I study of TAS-115 consisted of three parts: part 1 (TAS-115 was administered orally once daily [SID]); part 2 and an expansion part (SID in a 5 days on/2 days off [5-on/2-off] schedule for 21 days per cycle). In part 1 (200-800 mg SID administered to 21 patients), systemic exposure after single administration increased almost dose-proportionally. Three dose-limiting toxicities (DLTs) were observed in three patients: grade 3 rash (650 mg), thrombocytopenia with bleeding, and rash (800 mg). The maximum tolerated dose (MTD) was determined as 650 mg SID. In part 2, the 5-on/2-off schedule was evaluated at the MTD to improve treatment exposure. No DLTs were observed and no patients required treatment interruption in cycle 1. During part 2 and the expansion part (N = 61), grade ≥3 treatment-related adverse events were reported in 47 patients, with neutropenia (24.6%), hypophosphatemia (21.3%), anemia, and thrombocytopenia (14.8% each), and leukocytopenia (11.5%) occurring in ≥10% of patients. The best overall response was stable disease in 31 of 82 patients (37.8%). An apparent reduction in fluorodesoxyglucose-uptake and bone scan index was observed in some patients. TAS-115 was generally well tolerated, with manageable toxicities and recommended phase II dose was estimated as 650 mg SID, 5-on/2-off. Furthermore, promising antitumor activity was observed.

Foot allergic contact dermatitis to mixed dialkyl thioureas.

A 12-year-old boy presented with severe, bilateral foot dermatitis. Extended patch testing was performed, revealing a significant positive reaction to mixed dialkyl thioureas. A thorough review of his history revealed that he was likely being exposed through his neoprene taekwondo shoes. After implementation of allergen avoidance measures, his dermatitis resolved. This case emphasizes awareness of potential allergen exposures and offers helpful avoidance strategies.

Chrysin ameliorates ANTU-induced pulmonary edema and pulmonary arterial hypertension via modulation of VEGF and eNOs.

Alpha-naphthylthiourea (ANTU), a rodenticide induces lung toxicity. Chrysin a flavonoid possesses antioxidant, anti-inflammatory, and antihypertensive potential. The aim of this study was to evaluate the efficacy of chrysin against ANTU-induced pulmonary edema (PE) and pulmonary arterial hypertension (PAH) in laboratory rats. Sprague-Dawley rats were used to induce PE (ANTU, 10 mg/kg, ip) and PAH (ANTU, 5 mg/kg, ip, 4 weeks). Animals were treated with chrysin (10, 20, and 40 mg/kg) and various biochemical, molecular, and histological parameters were evaluated. Acute administration of ANTU induces PE revealed by significant (P < 0.05) increase in relative lung weight, pleural effusion volume, lung edema, bronchoalveolar lavage fluid cell counts, total protein, 5-hydroxytryptamine (5-HT), lactate dehydrogenase (LDH), and γ-glutamyl transferase (GGT), whereas pretreatment with chrysin (20 and 40 mg/kg, ip) significantly (P < 0.05) attenuated these ANTU-induced biochemical and histological alterations. Repeated administration of ANTU caused induction of PAH evaluated by significant (P < 0.05) alterations in electrocardiographic, hemodynamic changes, and left ventricular function, whereas chrysin (20 and 40 mg/kg, p.o.) treatment significantly (P < 0.05) attenuated these alterations. ANTU-induced hematological and serum biochemical (aspartate transaminase, alanine transaminase, LDH, and creatinine kinase MB) alterations were significantly (P < 0.05) inhibited by chrysin. It also significantly (P < 0.05) decreased elevated levels of oxido-nitrosative stress in the right ventricle (RV) and lung. Chrysin significantly (P < 0.05) attenuated downregulated endothelial nitric oxide synthase and upregulated vascular endothelial growth factor messenger RNA and protein expressions both in the RV and pulmonary artery. Chrysin inhibited ANTU-induced PE and PAH via modulation of inflammatory responses (5-HT, LDH, and GGT), oxido-nitrosative stress, and VEGF and eNOs levels.

Isothiocyanates are important as haptens in contact allergy to chloroprene rubber.

BACKGROUND: Contact allergy to chloroprene rubber products is well known. Thiourea compounds are considered the cause of allergy. Diethylthiourea commonly occurs in this type of product and can decompose to the sensitizer ethyl isothiocyanate. OBJECTIVES: To investigate the clinical importance of degradation products and metabolites from organic thioureas in contact allergy to chloroprene rubber with a focus on isothiocyanates and isocyanates. METHODS: Patients with contact allergy to diphenylthiourea were patch tested with phenyl isothiocyanate and phenyl isocyanate. Patients with known contact allergy to diethylthiourea were retested with diethylthiourea, while chemical analyses of their chloroprene rubber products were performed. The stability of diethylthiourea, diphenylthiourea and dibutylthiourea in patch-test preparations was investigated. Liquid chromatography/mass spectrometry and solid-phase microextraction/gas chromatography were used for determination of organic thioureas and isothiocyanates. RESULTS: All patients allergic to diphenylthiourea reacted to phenyl isothiocyanate, two of eight reacted to phenyl isocyanate and six of eight reacted to diphenylthiourea. Four patients allergic to diethylthiourea reacted at retest; diethylthiourea was detected in all chloroprene rubber samples, with levels of 2-1200 nmol cm-2 . At 35 °C, ethyl isothiocyanate was emitted from all samples. Patch-test preparations of diethylthiourea, diphenylthiourea and dibutylthiourea all emitted the corresponding isothiocyanate, with diethylthiourea showing the highest rate of isothiocyanate emission. CONCLUSIONS: Thiourea compounds are degraded to isothiocyanates, which are generally strong or extreme sensitizers, thus acting as prehaptens. This process occurs in both chloroprene rubber products and patch-test preparations. Positive reactions to phenyl isocyanate indicate cutaneous metabolism, as the only known source of exposure to phenyl isocyanate is through bioactivation of diphenylthiourea.

Taste genetics and gastrointestinal symptoms experienced in chronic kidney disease.

BACKGROUND/OBJECTIVES: It is unknown what causes uraemic symptoms in renal disease. Chronic kidney disease (CKD) patients are known to have increased levels of urea, sodium, potassium and phosphate in their saliva compared with those without renal disease. The present cross-sectional study investigated associations between known genetic traits of taste and self-reported upper gastrointestinal (GI) symptoms experienced in CKD patients with the changes in saliva composition found in renal failure. SUBJECTS/METHODS: Fifty-six CKD patients (35 males, 21 females, age 67±14 years), with stages 4 and 5 renal failure, selected from a tertiary hospital renal outpatient clinic participated in this study. Subjects answered a questionnaire to assess upper GI symptoms and tested for the genetic taste recognition thresholds of thiourea, phenylthiocarbamide and sodium benzoate. Saliva samples were collected to determine biochemical composition. Possible associations between genetic taste variations, saliva composition and upper GI symptoms were investigated. RESULTS: Of the 56 patients enroled, 29 (52%) reported major upper GI uraemic symptoms, whereas 27 (48%) had no symptoms or only minor complaints of dry mouth. There was a strong association between the symptomatic burden a patient experienced and the genetic ability to taste thiourea (P<0.0003). Uraemic symptoms of taste changes (P<0.004) and nausea (P<0.002) were found to be related to a patient's genetic ability to taste thiourea. CONCLUSIONS: This study provides evidence that the genetic ability to taste thiourea as bitter, in combination with the increase in active compounds found in CKD patient's saliva, impacts on the uraemic upper GI symptoms experienced.

Targeted testing with diethylthiourea often reveals clinically relevant allergic contact dermatitis caused by neoprene rubber.

BACKGROUND: Diethylthiourea is widely used in the rubber industry, particularly in neoprene rubber, and may cause allergic contact dermatitis. However, as thiourea allergens are not part of the European baseline series, the diagnosis of allergic contact dermatitis caused by thiourea compounds depends on clinical suspicion and aimed testing. OBJECTIVES: The aims of this study were to evaluate the occurrence of sensitization to diethylthiourea during a 19-year period by using data from the Allergen Bank database at the Department of Dermatology and Allergy Centre, Odense University Hospital, and to evaluate whether the yield of aimed patch tests with diethylthiourea differed between the dermatologists in practice and those working in the dermatology department. PATIENTS AND METHODS: A total of 239 patients were patch tested with diethylthiourea 1% in petrolatum obtained from the Allergen Bank. The records for patients with positive reactions were evaluated retrospectively. RESULTS: One hundred and fifty-one patients were tested by 27 different dermatologists in private practice, and positive reactions were found in 16% (24/151) of the patients; 88 patients were tested at the dermatology department, and positive reactions were found in 15% (13/88). Thus, 15% (37/239) had positive patch test reactions to diethylthiourea, all with current clinical relevance and all strong. CONCLUSION: Clinical suspicion of neoprene rubber allergy and subsequent aimed patch testing with diethylthiourea give a high yield of clinically relevant allergic patch test reactions for both dermatologists in practice and dermatologists in the hospital department.

A novel vaginal microbicide containing the rationally designed anti-HIV compound HI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea]).

INTRODUCTION: A focal point in contemporary research aimed at preventing the heterosexual spread of AIDS has been the development of intravaginal anti-HIV microbicides to curb the mucosal human immunodeficiency virus type 1 (HIV-1) transmission. AREAS COVERED: This article reviews the preclinical activity and safety profile of the thiophene thiourea PETT derivative, HI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea]). HI-443 is a rationally designed non-nucleoside reverse transcriptase inhibitor (NNRTI) with unprecedented activity against primary clinical HIV-1 isolates with NRTI or NNRTI resistance, multidrug resistance as well as non-B envelope subtypes of HIV-1. HI-443 exhibited a favorable toxicity and pharmacokinetics profile following oral, intraperitoneal or intravenous administration in rodents and a favorable safety profile after repeated intravaginal dosing via a gel formulation in rabbits and pigs. HI-443 did not induce the secretion of pro-inflammatory cytokines and chemokines by three-dimensional reconstituted human vaginal epithelia integrating Langerhans cells ex vivo or in the in vivo porcine model at therapeutic dose levels. Intravaginally administered HI-443 prevented vaginal transmission of a drug-resistant clinical HIV-1 isolate in the surrogate Hu-PBL-SCID mouse model of AIDS. EXPERT OPINION: The discovery of HI-443 as a non-spermicidal broad-spectrum antiretroviral agent represents a significant step forward in the development of a prophylactic microbicide without contraceptive activity for curbing heterosexual HIV transmission.

Salubrinal, an eIF2α dephosphorylation inhibitor, enhances cisplatin-induced oxidative stress and nephrotoxicity in a mouse model.

Although cisplatin attacks various tumors with remarkable efficacy, its clinical usage has been limited by its side effects, particularly nephrotoxicity. Salubrinal, a selective eukaryotic translation initiation factor 2 subunit α (eIF2α) dephosphorylation inhibitor, has been found to protect cells from endoplasmic reticulum (ER)-stress-induced cytotoxicity. In this study, we hypothesized that salubrinal would protect against cisplatin-induced nephrotoxicity in a mouse model. Cisplatin treatment significantly increased serum blood urea nitrogen and creatinine levels, renal kidney injury marker (kim-1) mRNA expression, renal cell apoptosis, and renal histopathological changes in mice. Unexpectedly, administration of salubrinal significantly enhanced the cisplatin-induced nephrotoxicity in mice. Salubrinal by itself did not induce alterations in the function or histomorphology of mouse kidneys. Salubrinal significantly enhanced the phosphorylation of eIF2α, the protein expression of activating transcription factor 4 and CCAAT/enhancer binding protein homologous protein, and the cleavage of caspases 12, 9, and 3 in the kidneys of cisplatin-treated mice. Moreover, salubrinal enhanced the cisplatin-induced oxidative stress in the kidneys. The antioxidant N-acetylcysteine significantly reversed the increased renal lipid peroxidation, activated renal caspase cascade, and increased blood BUN and creatinine in cisplatin-alone- or cisplatin plus salubrinal-treated mice. These findings suggest that salubrinal aggravates cisplatin-induced nephrotoxicity through the enhancement of oxidative stress and ER stress-related cell apoptosis.

Sensitization to thiourea derivatives among Finnish patients with suspected contact dermatitis.

BACKGROUND: Thiourea derivatives in rubber products may induce contact sensitization and allergic contact dermatitis. Sensitization is most often from neoprene rubber, but the multitude of possible sensitizing products has remained poorly characterized. OBJECTIVE: The aim of this study was to collect information on the occurrence of thiourea-related contact allergy and to show novel sources of sensitization. PATIENTS AND METHODS: A mixture of dibutyl-, diethyl-, and diphenylthiourea was included in patch test baseline series in five Finnish dermatology clinics during 2002-2007. In addition, an extended series of rubber chemicals was tested in patients with suspected rubber allergy. Sources of sensitization to thioureas were analysed in sensitized patients. RESULTS: Thiourea mix yielded positive patch test reactions in 59 of 15,100 patients (0.39%); 33/59 patients were also tested with individual rubber chemicals. Diethylthiourea was positive in 24/33, diphenylthiourea in 5, and dibutylthiourea in 1 patient. The most common sources of sensitization included various neoprene-containing orthopaedic braces, sports equipment, and foot wear. CONCLUSIONS: The sources of sensitization to thiourea chemicals were detected in most cases. These sources comprise a heterogenous group of products extending from orthopaedic materials to sports equipment.